Hee Siow-Wey, Chang Yi-Cheng, Su Lynn, Chen Ing-Jung, Jeng Yung-Ming, Hsieh Meng-Lun, Chang Yu-Chia, Li Fu-An, Liao Daniel, Chen Shiau-Mei, Chuang Lee-Ming
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan.
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100225, Taiwan.
iScience. 2023 Sep 22;26(10):107997. doi: 10.1016/j.isci.2023.107997. eCollection 2023 Oct 20.
15-keto-PGE is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE, through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response.
15-酮基前列腺素E是具有抗炎特性的类二十烷酸之一。在本研究中，我们证明15-酮基前列腺素E在翻译后分别修饰活化B细胞核因子κB（NF-κB）亚基p105/p50和p65的半胱氨酸59和半胱氨酸120位点，从而抑制巨噬细胞中NF-κB信号通路的激活。在喂食高脂高糖饮食（HFHSD）的小鼠中，15-酮基前列腺素E治疗降低了促炎细胞因子和空腹血糖水平。在由长期HFHSD诱导的非酒精性脂肪性肝炎（NASH）小鼠中，15-酮基前列腺素E治疗显著减轻肝脏炎症，降低血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，并抑制巨噬细胞浸润。它还减小了脂滴大小并下调了脂肪生成的关键调节因子。这些发现突出了15-酮基前列腺素E通过修饰NF-κB在预防脂肪性肝炎发生和发展方面的潜力，强调了内源性脂质介质在炎症反应中的重要性。
